Antibody-protein conjugates as inhibitors of HIV/AIDS

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Abstract

During FY2025 we achieved a major milestone in the development of glycan-targeting antibody-lectin conjugates by demonstrating, for the first time, in vivo protection from HIV challenge in a humanized mouse model. Building on previous work, we engineered and tested monomeric griffithsin (mGRFT) fused to the Fc domain of human IgG1 (mGRFT-Fc). Two versions were produced: one in E. coli (non-glycosylated) and one in Expi293 mammalian cells (mGRFT-Fcglyc), which contains the essential Fc glycan at Asn297 required for Fc receptor engagement. Both constructs retained high-affinity binding to gp120/gp140 and demonstrated picomolar HIV neutralization across a panel of 15 clinical strains. Pharmacokinetic studies in rats showed that mGRFT-Fc had a significantly extended plasma half-life (~30 hours) compared to GRFT (~7.5 hours), due to efficient FcRn-mediated recycling. Glycosylated mGRFT-Fcglyc bound FcγRI and FcγRIIIa receptors and triggered antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based assays. These immune functions were absent in the non-glycosylated form. In the HIV challenge study using CD34+ humanized mice, a single dose of mGRFT-Fcglyc protected two-thirds of the animals from infection over an 8-week period. Importantly, unlike GRFT, mGRFT-Fcglyc conferred dual protection by both neutralizing virus and eliminating infected cells through Fc-mediated immune responses. This establishes that a glycan-targeting biologic alone can confer in vivo protection against HIV infection. These findings, published in Molecular Therapy (Kumariya et al., 2025), validate the design concept and therapeutic potential of antibody-lectin conjugates. Ongoing efforts include evaluating post-exposure efficacy, scaling up mammalian expression, and expanding to mucosal delivery